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Transcript of Baroreflex Activation Therapy for the Treatment of Heart Failure with a Reduced Ejection Fraction...
Baroreflex Activation Therapy for the Treatment of Heart Failure with a Reduced Ejection Fraction
William Abraham, MD1, Michael Zile, MD2, Fred Weaver, MD3, Christian Butter, MD4, Anique Ducharme, MD5, Marcel
Halbach, MD6, Didier Klug, MD7, Eric Lovett, PhD8, Jochen Müller-Ehmsen, MD9, Jill Schafer, MS10, Michele Senni, MD11, Vijay Swarup, MD12, Rolf Wachter, MD13, William Little, MD14;
on behalf of the BAT for HFrEF Study Group
1Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH, USA; 2Medical University of South Carolina, Charleston, South Carolina; Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina, USA; 3Division of Vascular Surgery and Endovascular Therapy, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; 4Department of Cardiology, Immanuel Heart Center Bernau - Medical School Brandenburg, Bernau, Germany; 5Montreal Heart Institute, University of Montréal, Montreal, Quebec, Canada; 6Department of Internal Medicine III, University Hospital of Cologne,
Cologne, Germany; 7Department of Cardiology A, University Hospital, Lille, France; 8Department of Research, CVRx, Inc., Minneapolis, Minnesota, USA; 9Department of Medicine #, Asklepios Klinik Altona, Hamburg, Germany; 10Department of Statistics, NAMSA, Inc., Minneapolis, Minnesota, USA; 11Cardiovascular
Department, Ospedale Papa Giovanni XXIII, Bergamo, Italy; 12Department of Electrophysiology, Arizona Heart Hospital, Phoenix, Arizona, USA; 13Clinic for Cardiology and Pneumology, University Medicine Göttingen and German Cardiovascular Research Center (DZHK), Göttingen, Germany; 14Division of Cardiology,
University of Mississippi Medical Center, Jackson, Mississippi, USA
Background
Increased sympathetic and decreased parasympathetic activity contribute to heart failure symptoms and disease progression
Baroreflex activation therapy (BAT) results in centrally mediated reduction of sympathetic outflow and increased parasympathetic activity
Preliminary observations suggest that BAT improves clinical status and outcomes in patients with heart failure and a reduced ejection fraction (HFrEF)1
1Gronda E, et al. Eur J Heart Fail 2014; 16:977-983.
Integrated Autonomic Nervous System Response
Inhibits Sympathetic ActivityEnhances Parasympathetic Activity
Carotid Baroreceptor Stimulation
↓ HR
↓ Remodeling
↑ Vasodilation
↓ Elevated BP
↑ Diuresis
↓ Renin secretion
The Baroreflex as a Therapeutic Target
Objective: Evaluate the efficacy and safety of the CVRx neoTM Baroreflex Activation Therapy System in subjects with chronic heart failure and reduced ejection fraction
Design: Multi-national, prospective, randomized controlled trial
Subjects randomized 1:1 to receive BAT plus optimal medical therapy or optimal medical therapy alone
Enrollment in the US, Germany, Italy, France and Canada
BAT for HFrEF: Study Objective and Design
NYHA Functional Class III
Left ventricular ejection fraction ≤ 35%
Six-minute hall walk distance 150 - 400 m
On stable optimal medical therapy for at least 4 weeks prior to baseline assessment
No restriction on QRS, concomitant devices*, or AF
* ≥ 6 months of CRT therapy in patients with CRT
BAT for HFrEF: Key Enrollment Criteria
Oversight Details
Data Monitoring Committee (DMC) Full review every 6 months
Heart Failure Steering Committee Biweekly meetings
Independent Clinical Monitors 100% source verification
Clinical Events Committee Hospitalization adjudication
Independent Biostatistician All statistical analyses
Adverse Event Committee Adverse event adjudication
BAT for HFrEF: Trial Oversight
Randomized
146
BAT
76
Med Mgmt
70
Activated
71
Withdrawn
5
“Activated”
69
Death
1
BAT for HFrEF: Subject Disposition
To receive a randomization assignment, the intended date of BAT initiation was identified as the “activation date”
The activation date determined the schedule for all follow-up visits for both Med Mgmt and BAT group
Variable BAT (n=71)
Med Mgmt(n=69)
Race: Caucasian 82% 90% Gender: Female 13% 16% NYHA: Class III 99% 100% Age (years) 64 ± 11 66 ± 12 SBP (mmHg) 115 ± 18 119 ± 17 DBP (mmHg) 72 ± 11 73 ± 11 HR (bpm) 73 ± 11 75 ± 12 LVEF (%) 24 ± 7 25 ± 7 eGFR (mL/min) 58 ± 21 59 ± 19 NT-pro BNP (pg/mL)* 1422 [455, 4559] 1172 [548, 2558] 6 Minute Hall Walk (m) 297 ± 79 308 ± 85 MN Living with HF QOL† 51 ± 21 43 ± 22 Number of Meds 4.8 ± 1.6 4.4 ± 1.9 Coronary Artery Disease 66% 68% History of Atrial Fibrillation 45% 44% Chronic Kidney Disease 34% 25%
HF hospitalizations prior 6 Mo (days/pt/year) 7.0 ± 21 2.4 ± 9
*Median [IQR]†p≤0.05 between groups
BAT for HFrEF: Baseline Demographics
VariableBAT
(n=71)Med Mgmt
(n=69)
Number of Meds 4.8 4.4
ACE/ARB 80% 81%
Beta-Blocker 87% 85%
Calcium Channel Blocker 6% 9%
Digitalis 21% 10%
Diuretic† 93% 78%
Ivabradine 4% 2%
MRA 59% 50%
CRT 34% 30%
ICD 89% 86%
†p≤0.05 between groups
BAT for HFrEF: Baseline Medications
System- or Procedure-Related Major Adverse Neurological or Cardiovascular Events (MANCE) at 6 months
97% Event-Free Rate71 Subjects Implanted
BAT for HFrEF: Primary Safety Endpoint
2 Pocket hematomas (1 and 7 days from implant)
General Surgical 2 Urinary retention / urinary tract infection 1 Pneumothorax due to improper subcutaneous needle placement 1 Cervical Neuralgia*
Cardiovascular (All events began during or within 24 hours of implant) 2 Non-sustained atrial arrhythmias 1 Transient bradycardia 1 Transient hypotension 1 Transient worsening heart failure
No death, stroke, or cranial nerve injury All but one* occurred within 7 days of implant and
recovered with no residual effect:
Other System- or Procedure-Related Complications
BAT for HFrEF: Other Safety Observations
BAT does not cause hypotension in patients with advanced heart failure No reports of symptomatic hypotension
SBP significantly increased in BAT group; DBP unchanged
BAT is compatible with co-existing cardiac rhythm management devices
Change from baseline to 6 months in New York Heart Association Functional Class Rank Minnesota Living with Heart Failure Quality of Life Score Six-Minute Hall Walk (6-MHW) Distance Serum Biomarker (NT-proBNP) Left Ventricular Ejection Fraction Hospitalizations (Days) for Worsening Heart Failure*
BAT for HFrEF: Efficacy Endpoints
*Baseline defined as 6 months prior to enrollment
BAT Significantly Improves NYHA Class
BAT Significantly Improves Quality of Life Score
BAT Significantly Improves 6-MHW Distance
BAT Significantly Reduces NT-proBNP Levels
Non-parametric (median [IQR])
Effect of BAT on LV Ejection Fraction
Global Randomized Clinical Trial – HF HospitalizationEffect of BAT on Number of Hospitalization Days for Heart Failure
*p≤0.10; **p≤0.05
†RR – Relative Reduction adjusted for 6 months Pre-Enrollment Heart Failure Hospitalizations (Negative Binomial Model)
VariableBAT
(n=57)Med Mgmt
(n=50)
Difference
Mean ± SE
HF Hospitalization Days per Year
6 Months Pre-Enrollment 6.95 ± 20.7 2.40 ± 8.6 4.55 ± 34
6 Months Post Enrollment 0.67 ± 2.5 2.48 ± 7.4 -1.82* ± 1
Change from Pre to Post -6.28** ± 2.7 0.08 ± 1.7 -6.36** ± 3
Negative Binomial 6M Post 0.38 2.10 82% RR†*
Concordance of Results Support BAT Efficacy in HFrEF
Difference p value Favors
NYHA (% impoved) 31 < 0.01 BAT
MLWHF QoL Score (points) 20 <0.001 BAT
6-MHW Distance (m) 58 <0.01 BAT
NT-proBNP (pg/ml)* 342 0.02 BAT
LVEF (absolute %) 2.5 0.15 BAT
Hospitalization Days for Worsening HF (days/pt/yr)
6.4 0.05 BAT
* Median
BAT for HFrEF: Summary Baroreflex Activation Therapy is safe in HFrEF patients
No system- or procedure-related deaths
Few and short-lived complications; complication rate comparable to established HF device therapies
No hypotension
BAT significantly improves NYHA Class, quality of life score, exercise capacity, NT-proBNP, and possibly the burden of heart failure hospitalizations
If these observations are confirmed in a larger study, BAT may offer a new addition for the treatment of advanced HFrEF patients
Baroreflex Activation Therapy for the Treatment of Heart Failure with a Reduced Ejection Fraction
Manuscript online today at JACC Heart Failure http://heartfailure.onlinejacc.org